Posted by With advanced age, alterations of specific gut-derived metabolites such as aromatic amino acid derivatives might contribute to CVD through prolonged oxidative stress and inflammation. One such example is phenylacetic acid (PAA) and its derivative phenylacetylglutamine (PAGln), which are produced from phenylalanine by commensal microbial porA or ppfor genes. These metabolites are positively associated with cardiovascular and all-cause mortality in patients with chronic kidney disease (CKD) and heart failure.
In this study, it was confirmed that there exist a causal link between gut microbiota and aortic endothelial senescence, identifying Clostridium sp. ASF356 and its byproduct PAA as contributors to vascular dysfunction. Clostridium sp. ASF356, harboring the ppfor gene, regulates circulating PAA, a key factor in endothelial cell senescence and angiogenic incompetence in aging. The authors discovered that PAA induces cellular senescence in aortic endothelial cells through H2O2-regulated senescence-associated secretory phenotype (SASP). It was proposed that sodium acetate acts as a senomorphic and redox-homeostatic agent with pro-angiogenic potential to aid recovery from ischemic vascular diseases in older adults.
However, the microbiome in the gut also produces substances that are beneficial to vascular health. Short-chain fatty acids such as acetate, which are produced by fermentation of dietary fibers and polysaccharides in the intestine, act as natural rejuvenating agents. The research group used in-vitro experiments to show that adding sodium acetate can restore the function of aged vascular endothelial cells. When analyzing intestinal bacteria, they found that the number of bacteria that produce such rejuvenating agents decreases with age.
Saeedi Saravi, S.S., Pugin, B., Constancias, F. et al. Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging. Nat Aging (2025). https://doi.org/10.1038/s43587-025-00864-8
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